Role of intrarenal endothelin 1, endothelin 3, and angiotensin II expression in chronic cyclosporin A nephrotoxicity in rats

Endothelin 1 (Et1) is widely expressed in the kidney and is related to seve ral functions and to pathological conditions with progression towards scler osis. The function of endothelin 3 (Et3) at the renal level is debatable, b ut it could have an important regulatory function in the reabsorption of wa ter through its action on tubular type B receptors. Angiotensin II has rece ntly been implicated as the principal factor responsible for the progressio n of interstitial fibrosis induced by cyclosporin A (CsA). We investigated this relationship in vivo and analyzed the modifications induced by CsA tox icity in Sprague-Dawley rats treated with 25 mg/kg/day of CsA for 28 and 56 days. Immunohistochemical methods and molecular analysis were used to stud y the expression of Et1 and Et3 and immunohistochemistry alone to determine the intrarenal expression of angiotensin II. Rats treated with CsA develop ed chronic nephrotoxicity lesions; semiquantitative analyses of hyaline art eriolopathy revealed that the passage of time affected the extent of this l esion and led to the diminution of the total glomerular area. Immunohistoch emical results showed that chronic CsA treatment induced moderate secretion of Et1 and Et3 at tu bu lar and glomerular levels and that the local expre ssion of angiotensin II in the treatment groups was more evident than in co ntrol animals. Besides, the mRNA levels of pre-proEt3 showed a dramatic inc rease from 28 days after CsA treatment (control group 0.07 +/- 0.11 vs. CsA group 0.48 +/- 0.11, p < 0.01), while the mRNA levels of pre-proEt1 increa sed from 56 days (control group 0.15 +/- 0.05 vs. CsA group 0.34 +/- 0.09, p < 0.05). At 28 days, renal lesions correlated strongly with the mRNA leve ls of Et3 (r > 0.50, p < 0.01). However, at 56 days, the key finding was th e strong correlation of the most important analytical, histological, and im munohistochemical parameters of CsA nephrotoxicity with Et1 mRNA levels (r > 0.50, p < 0.01). These results support the hypothesis that the clinical a nd morphological phenomena linked with CsA nephrotoxicity are related to hy persecretion of endothelins and local expression of angiotensin II in the o uter medulla and medullary rays; Et3 and angiotensin II are the first to ac t, followed subsequently by Et1. Copyright (C) 2000 S. Karger AG, Basel.